Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
for maintenance.
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
for maintenance.
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
for maintenance.
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
for maintenance.
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
for maintenance.
twitter

MetaCyc Polypeptide: pyruvate dehydrogenase E1 component α subunit (somatic)

Gene: PDHA1 Accession Number: HS05573 (MetaCyc)

Synonyms: PHE1A, PDHE1-A type I

Species: Homo sapiens

Component of:
pyruvate dehydrogenase E1 component (somatic) (summary available)
pyruvate dehydrogenase complex (extended summary available)

Summary:
cDNAs encoding the α subunit of human pyruvate dehydrogenase were isolated from multiple sources and sequenced [Dahl87a, Koike88, De88b, Ho89a]. The protein contains three serine phosphorylation sites.

The PDHA1 gene encoding the enzyme is located on chromosome X and contains 11 exons [Maragos89, Koike90].

Defects in the gene coding for the α subunit of pyruvate dehydrogenase are associated with a variety of clinical symptoms, often of a severe character.

Locations: mitochondrion

Map Position: [18,028,310 -> 18,044,231]

Molecular Weight of Polypeptide: 43.296 kD (from nucleotide sequence)

Unification Links: ArrayExpress:P08559 , DIP:DIP-37652N , Entrez-gene:5160 , Mint:MINT-3006251 , PhosphoSite:P08559 , PhylomeDB:P08559 , Pride:P08559 , Protein Model Portal:P08559 , SMR:P08559 , String:9606.ENSP00000394382 , UniProt:P08559

Relationship Links: InterPro:IN-FAMILY:IPR001017 , InterPro:IN-FAMILY:IPR017597 , PDB:Structure:1NI4 , PDB:Structure:2OZL , PDB:Structure:3EXE , PDB:Structure:3EXF , PDB:Structure:3EXG , PDB:Structure:3EXH , PDB:Structure:3EXI , Pfam:IN-FAMILY:PF00676

Gene-Reaction Schematic: ?

GO Terms:

Biological Process: GO:0006084 - acetyl-CoA metabolic process
GO:0006096 - glycolytic process
GO:0008152 - metabolic process
Molecular Function: GO:0004739 - pyruvate dehydrogenase (acetyl-transferring) activity
GO:0016491 - oxidoreductase activity
Cellular Component: GO:0005739 - mitochondrion

Credits:
Imported from HumanCyc 04-Nov-2011 by Caspi R , SRI International
Revised 04-Nov-2011 by Caspi R , SRI International


Subunit of: pyruvate dehydrogenase E1 component (somatic)

Species: Homo sapiens

Subunit composition of pyruvate dehydrogenase E1 component (somatic) = [PDHB]2[PDHA1]2
         pyruvate dehydrogenase E1 component β subunit = PDHB (summary available)
         pyruvate dehydrogenase E1 component α subunit (somatic) = PDHA1 (summary available)

Component of: pyruvate dehydrogenase complex (extended summary available)

Summary:
The α2β2-heterotetrameric human pyruvate dehydrogenase, one of the three main components of the pyruvate dehydrogenase complex, utilizes the thiamin pyrophosphate cofactor to cleave the Cα-C(=O) bond of pyruvate, followed by reductive acetyl transfer to lipoyl-dihydrolipoamide acetyltransferase (the E2 component of the pyruvate dehydrogenase complex).

The crystal structure of the holo-form of the E1 enzyme was resolved at 1.95-A resolution [Ciszak03].

Credits:
Created in HumanCyc 04-Nov-2011 by Caspi R , SRI International
Imported from HumanCyc 04-Nov-2011 by Caspi R , SRI International


Enzymatic reaction of: pyruvate dehydrogenase

EC Number: 1.2.4.1

pyruvate + a [pyruvate dehydrogenase E2 protein] N6-lipoyl-L-lysine + H+ <=> a [pyruvate dehydrogenase E2 protein] N6-S-acetyldihydrolipoyl-L-lysine + CO2

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

This reaction is reversible.

In Pathways: pyruvate decarboxylation to acetyl CoA

Credits:
Imported from HumanCyc 04-Nov-2011 by Caspi R , SRI International


Subunit of: pyruvate dehydrogenase complex

Species: Homo sapiens

Subunit composition of pyruvate dehydrogenase complex = [(PDHB)2(PDHA1)2]30[DLAT]60[(PDHX)][(DLD)2]6
         pyruvate dehydrogenase E1 component (somatic) = (PDHB)2(PDHA1)2 (summary available)
                 pyruvate dehydrogenase E1 component β subunit = PDHB (summary available)
                 pyruvate dehydrogenase E1 component α subunit (somatic) = PDHA1 (summary available)
         pyruvate dehydrogenase E2 component = DLAT (extended summary available)
         pyruvate dehydrogenase E3-binding protein = (PDHX)
                 pyruvate dehydrogenase protein E3 component, mitochondrial = PDHX
         dihydrolipoyl dehydrogenase = (DLD)2 (extended summary available)
                 dihydrolipoyl dehydrogenase monomer = DLD

Summary:
The pyruvate dehydrogenase complex (PDH) is a large enzyme complex made up of multiple copies of three enzymes: E1 (20-30 copies of pyruvate dehydrogenase, an α2β2 heterotetramer), 60 copies of E2 (dihydrolipoamide acetyltransferase), and six homodimers of E3 (dihydrolipoamide dehydrogenase), together with the E3 binding protein, which is involved in the interaction between the E2 and E3 subunits.

Within the PDH complex, the E2 subunit forms the structural core and accepts acetyl groups from E1 and transfers them to coenzyme A. The irreversible decarboxylation of pyruvate and its conversion to acetyl-CoA by the PDH complex precedes the entry of glucose carbon into the tricarboxylic acid (TCA) cycle. This process is fundamental to the aerobic oxidation of glucose and is of particular importance in the brain where it is the obligatory pathway for energy generation under normal conditions [McWilliam10].

The mitochondrial pyruvate dehydrogenase complex (PDC) plays a critical fuel selection role in determining whether glucose-linked substrates are converted to acetyl-CoA. When carbohydrate stores are reduced, mammalian PDC activity is down-regulated and limits the oxidative utilization of glucose in most non-neural tissues.

Four pyruvate dehydrogenase kinase (PDK) isozymes and two pyruvate dehydrogenase phosphatase (PDP) isoforms control the activity state of PDC by determining the proportion of the pyruvate dehydrogenase (E1) component that is in the active, nonphosphorylated state [Roche03].

Credits:
Created in HumanCyc 04-Nov-2011 by Caspi R , SRI International
Imported from HumanCyc 04-Nov-2011 by Caspi R , SRI International


Enzymatic reaction of: pyruvate dehydrogenase

EC Number: 1.2.1.-

pyruvate + coenzyme A + NAD+ <=> acetyl-CoA + CO2 + NADH

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

This reaction is reversible.

In Pathways: pyruvate decarboxylation to acetyl CoA

Exons/Introns:


References

Ciszak03: Ciszak EM, Korotchkina LG, Dominiak PM, Sidhu S, Patel MS (2003). "Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase." J Biol Chem 278(23);21240-6. PMID: 12651851

Dahl87a: Dahl HH, Hunt SM, Hutchison WM, Brown GK (1987). "The human pyruvate dehydrogenase complex. Isolation of cDNA clones for the E1 alpha subunit, sequence analysis, and characterization of the mRNA." J Biol Chem 262(15);7398-403. PMID: 3034892

De88b: De Meirleir L, MacKay N, Lam Hon Wah AM, Robinson BH (1988). "Isolation of a full-length complementary DNA coding for human E1 alpha subunit of the pyruvate dehydrogenase complex." J Biol Chem 263(4);1991-5. PMID: 2828359

Ho89a: Ho L, Wexler ID, Liu TC, Thekkumkara TJ, Patel MS (1989). "Characterization of cDNAs encoding human pyruvate dehydrogenase alpha subunit." Proc Natl Acad Sci U S A 86(14);5330-4. PMID: 2748588

Koike88: Koike K, Ohta S, Urata Y, Kagawa Y, Koike M (1988). "Cloning and sequencing of cDNAs encoding alpha and beta subunits of human pyruvate dehydrogenase." Proc Natl Acad Sci U S A 85(1);41-5. PMID: 3422424

Koike90: Koike K, Urata Y, Matsuo S, Koike M (1990). "Characterization and nucleotide sequence of the gene encoding the human pyruvate dehydrogenase alpha-subunit." Gene 93(2);307-11. PMID: 2227443

Maragos89: Maragos C, Hutchison WM, Hayasaka K, Brown GK, Dahl HH (1989). "Structural organization of the gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex." J Biol Chem 264(21);12294-8. PMID: 2745444

McWilliam10: McWilliam CA, Ridout CK, Brown RM, McWilliam RC, Tolmie J, Brown GK (2010). "Pyruvate dehydrogenase E2 deficiency: a potentially treatable cause of episodic dystonia." Eur J Paediatr Neurol 14(4);349-53. PMID: 20022530

Roche03: Roche TE, Hiromasa Y, Turkan A, Gong X, Peng T, Yan X, Kasten SA, Bao H, Dong J (2003). "Essential roles of lipoyl domains in the activated function and control of pyruvate dehydrogenase kinases and phosphatase isoform 1." Eur J Biochem 270(6);1050-6. PMID: 12631265


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Sun Dec 21, 2014, biocyc13.